Circulating Tumor Cells No Guide for Chemo

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Changing to alternative chemotherapy does not improve survival for patients with metastatic breast cancer who have elevated circulating tumor cell levels at follow-up assessment after a single cycle of first-line chemotherapy, a study found.

SAN ANTONIO -- Changing chemotherapy based on an early lack of circulating tumor cell response didn't improve outcomes in metastatic breast cancer, a cooperative group trial showed.

The strategy was associated with no hint of a survival advantage compared with maintaining the original first-line chemotherapy regimen despite a failure of the tumor cell count to fall below 5 per 7.5 mL of peripheral blood in the Southwest Oncology Group S0500 trial.

Progression-free survival was likewise similar at 3.5 months with a change and 4.6 months without (P=0.61), they added.

The idea was to "avoid unnecessary cumulative toxicities from a therapy that is presumably not working, and also ... potentially allow them to switch to another therapy, which might increase the odds that they would be on an effective therapy," Smerage explained at a press conference.

The strategy may have been hamstrung by allowing physician's choice of chemotherapy both initially and at the switch, resulting in "enormous" heterogeneity, commented conference co-director Peter Ravdin, MD, PhD, of the University of Texas Health Science Center at San Antonio.

"If the second-line therapy was uniform and very efficacious, then I would expect that switching early to that therapy would have enormous benefit," he said in an interview. "But this trial doesn't suggest we're ready."

The test used in the study isn't likely to become widely used based on prognostic information it offers alone, given the many other modalities available to provide that information, he added.

Whereas the early change in therapy had little impact, circulating tumor cell levels and how they changed were "highly prognostic."

Among the 595 patients eligible to enter the trial who had their blood drawn prior to starting first-line chemotherapy, 46% had fewer than five tumor cells per 7.5 mL of whole peripheral blood and so were simply observed for outcomes.

This arm had the best median overall survival, at 35 months.

The rest had circulating tumor cells measured again with the CellSearch System after one cycle of first-line chemotherapy.

Of those patients, the 57% whose circulating tumor cell count dropped below five per 7.5 mL blood after the first cycle stayed on that first-line chemotherapy until progression.

This group had the next-best survival figures, with a median overall survival of 23 months.

The remaining 123 patients with less of a circulating tumor cell response were randomized to either stay on their chemotherapy regimen or to switch to their physician's choice of alternate therapies.

These two groups together had dramatically poorer survival than the other groups, at a median 13 months. The difference among groups was significant at P<0.0001.

Smerage cautioned against interpreting the findings as an indication chemotherapy isn't effective for these patients.

Rather, they may need more aggressive strategies than tried in the trial, he suggested.

Those whose circulating tumor cell levels don't drop quickly with chemotherapy in the metastatic setting "are clearly at high risk," so physicians might consider not waiting to enroll these patients in trials with novel or targeted therapy, he explained.

Biologic therapy was also allowed during the study along with chemotherapy, and treatment changes could be made for intolerable toxicity or for a "holiday" from chemotherapy if no evidence of progression was found after 24 weeks.

Prior endocrine, bisphosphonate, and other biologic therapies like trastuzumab (Herceptin) were allowed in the trial, though prior chemotherapy in the metastatic setting or in the adjuvant setting within 12 months was not.

"Today we now have the ability to do much more in terms of molecular profiling of these cells," Smerage pointed out. "Whether it is looking at protein expression, RNA expression, looking for genetic mutations in these cells, even processes such as FISH are all possible in these cells in ways I hope will lead to better ability to predict the appropriate treatment strategies for these patients in a way simply counting cells doesn't appear to do."

For example, metastatic tumor cells could be tested for HER2 status in the the peripheral blood sample without requiring repeated biopsy, which would guide therapy, he noted.

Multiple smaller studies are ongoing to determine whether another large cooperative group trial is warranted.

"I'm optimistic that's going to happen," he concluded.

The study was funded by the National Cancer Institute, and in part by Veridex.

Smerage declared having no conflicts of interest to disclose.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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